The objective of this proposal is to investigate the mechanisms underlying the preferential uptake and sequestration of a chosen model compound in the lung. Results from this laboratory show that pretreatment of rabbits with agents such as piperonyl butoxide enhances the pulmonary uptake of the tricyclic antidepressant imipramine. Pretreatment with other secretolytic agents also enhances the pulmonary accumulation of drugs, imipramine and anorectic agents such as chlorphentermine. The increased secretory organelles of the type II cells as well as elevated levels of phospholipids coincidental with the enhanced drug uptake suggest a possible relationship between lung phospholipids and a number of amphiphilic drugs known to be preferentially accumulated in the lung. Pulmonary uptake and accumulation of model drugs such as imipramine, chlorphentermine and chlorpromazine will be characterized using isolated perfused rabbit lung preparations. Pulmonary uptake of their chlorinated or non-chlorinated drug congenors will also be examined. Using drug pretreatment protocols uptake and accumulation of the above drugs will be studied in relation to the lung phospholipid concentration. Investigations will include studies on the displacement of a previously sequestered drug following the uptake of another xenobiotic by the lung. Understanding the basic mechanisms governing the preferential sequestration and release of drugs by the lung are essential in clinical management of significant drug interactions and drug-induced pulmonary disease.